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Lin M, Mo Y, Li CM, Liu YZ, Feng XP. GRP78 as a potential therapeutic target in cancer treatment: an updated review of its role in chemoradiotherapy resistance of cancer cells. Med Oncol 2025; 42:49. [PMID: 39827214 DOI: 10.1007/s12032-024-02586-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 12/12/2024] [Indexed: 01/22/2025]
Abstract
GRP78 (Glucose-related protein 78, BiP/HSPA5) is commonly overexpressed in cancer cells. Acting as an activator of endoplasmic reticulum stress, GRP78 is involved in the resistance of cancer cells to injury. Current evidence suggests that GRP78 plays a significant role in the radiotherapy resistance and chemotherapy resistance of cancers, which is accomplished through a variety of complex pathways. These include the promotion of tumor stemness, inhibition of apoptosis, regulation of autophagy, maintenance of tumor microenvironment homeostasis, protection of dormant cells, evasion of senescence, counteraction of autoantibodies against GRP78, facilitation of DNA damage repair, suppression of ferroptosis, and modulation of metabolic reprogramming in tumor cells. Importantly, chemoradiotherapy resistance in cancers are the main reasons for treatment failure in patients, severely affecting their survival. Investigating the mechanisms of GRP78 in tumor therapeutic resistance is essential. In this article, we review the mechanisms by which GRP78 mediates cell survival and chemoradiotherapy resistance in cancers and provide an overview of clinical trials targeting GRP78 therapy.
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Affiliation(s)
- Min Lin
- Department of Oncology and Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Yan Mo
- Department of Oncology and Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Cheng-Min Li
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Ying-Zhe Liu
- Xiangya International Medical Center, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410013, China.
| | - Xue-Ping Feng
- Department of Oncology and Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410013, China.
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Wang W, Hashimi B, Wang P. Targeting ferroptosis: the role of non-coding RNAs in hepatocellular carcinoma progression and therapy. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03791-y. [PMID: 39820644 DOI: 10.1007/s00210-025-03791-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 01/06/2025] [Indexed: 01/19/2025]
Abstract
One of the most common tumors is hepatocellular carcinoma (HCC), and the prognosis for late-stage HCC is still not good. It is anticipated that improved outcomes would result from a deeper comprehension of the pathophysiology of HCC. Ferroptosis as a new discovered cell death type is linked to the progression of HCC and may be crucial for its detection, prevention, therapy, and prognosis. Numerous studies suggest that epigenetic alterations mediated by non-coding RNAs (ncRNA) might influence cancer cell susceptibility to ferroptosis. This study elucidates the processes of ferroptosis and delineates the paths by which ncRNAs influence HCC by modulating ferroptosis. Furthermore, it offers significant insights into ferroptosis-associated ncRNAs, intending to discover novel therapeutic approaches for HCC. It also explores innovative concepts for the future use of ncRNA-based ferroptosis-targeted therapeutics.
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Affiliation(s)
- Weijia Wang
- Department of Oncology, Qilu Hospital of Shandong University Dezhou Hospital (Dezhou People's Hospital), Shandong Province, China
| | - Behishta Hashimi
- Department of Midwifery, Jahan Institute of Health Sciences, Kabul, Afghanistan
| | - Ping Wang
- Department of Oncology, Yantaishan Hospital Affiliated to Binzhou Medical University, Yantai, Shandong Province, China.
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Mao G, Xu W, Jamil M, Zhang W, Jiao N, Liu Y. Exploring the Diagnostic and Prognostic Predictive Values of Ferroptosis-related Markers in Lung Adenocarcinoma. Curr Pharm Biotechnol 2025; 26:411-427. [PMID: 38523537 DOI: 10.2174/0113892010293337240312051931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/06/2024] [Accepted: 02/15/2024] [Indexed: 03/26/2024]
Abstract
BACKGROUND Lung Adenocarcinoma (LUAD), a common and aggressive form of lung cancer, poses significant treatment challenges due to its low survival rates. AIM To better understand the role of ferroptosis driver genes in LUAD, this study aimed to explore their diagnostic and prognostic significance, as well as their impact on treatment approaches and tumor immune function in LUAD. METHODS To accomplish the defined goals, a comprehensive methodology incorporating both in silico and wet lab experiments was employed. A comprehensive analysis was conducted on a total of 233 ferroptosis driver genes obtained from the FerrDB database. Utilizing various TCGA databases and the RT-qPCR technique, the expression profiles of 233 genes were examined. Among them, TP53, KRAS, PTEN, and HRAS were identified as hub genes with significant differential expression. Notably, TP53, KRAS, and HRAS exhibited substantial up-regulation, while PTEN demonstrated significant down-regulation at both the mRNA and protein levels in LUAD samples. The dysregulation of hub genes was further associated with poor overall survival in LUAD patients. Additionally, targeted bisulfite-sequencing (bisulfite-seq) analysis revealed aberrant promoter methylation patterns linked to the dysregulation of hub genes. RESULTS & DISCUSSION Furthermore, hub genes were found to participate in diverse oncogenic pathways, highlighting their involvement in LUAD tumorigenesis. By leveraging the diagnostic and prognostic potential of ferroptosis driver hub genes (TP53, KRAS, PTEN, and HRAS), significant advancements can be made in the understanding and management of LUAD pathogenesis. CONCLUSION Therapeutic targeting of these genes using specific drugs holds great promise for revolutionizing drug discovery and improving the overall survival of LUAD patients.
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Affiliation(s)
- Guoliang Mao
- Department of Pathology, Wannan Medical College First Affiliated Hospital, Yijishan Hospital, Wuhu, China
| | - Wuqin Xu
- Department of Pathology, Wannan Medical College First Affiliated Hospital, Yijishan Hospital, Wuhu, China
| | - Muhammad Jamil
- PARC Arid Zone Research Center, Dera Ismail Khan, Pakistan
| | - Wei Zhang
- Department of Pathology, Wannan Medical College First Affiliated Hospital, Yijishan Hospital, Wuhu, China
| | - Nanlin Jiao
- Department of Pathology, Wannan Medical College First Affiliated Hospital, Yijishan Hospital, Wuhu, China
| | - Yinhua Liu
- Department of Pathology, Wannan Medical College First Affiliated Hospital, Yijishan Hospital, Wuhu, China
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Jhade SK, Kalidoss K, Pathak PK, Shrivastava R. Artemisinin's molecular symphony: illuminating pathways for cancer therapy. Mol Biol Rep 2024; 52:95. [PMID: 39739138 DOI: 10.1007/s11033-024-10202-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 12/24/2024] [Indexed: 01/02/2025]
Abstract
Artemisinin (ART), a sesquiterpene lactone derived from the sweet wormwood plant (Artemisia annua), exhibits potent anti-malarial and anti-microbial properties, with emerging evidence suggesting its anticancer potential. This review delves into the molecular intricacies underlying ART's anticancer effects, elucidating its modulation of cell signaling pathways, induction of apoptosis and autophagy, and inhibition of angiogenesis crucial for cancer progression. Additionally, the review highlights ART's impact on oxidative stress and DNA damage within cancer cells, along with its potential synergistic effects with conventional cancer drugs to mitigate side effects. Despite notable strides, further elucidation of ART's mechanisms and clinical validation across diverse cancer types are necessary. Conclusively, this review provides a brief overview of the molecular foundation that makes ART a promising candidate for future cancer therapeutic strategies and emphasises the need for further research to fully comprehend the molecular complexity of ART-mediated cancer therapies.
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Affiliation(s)
- Sandeep Kumar Jhade
- Metabolomics and Proteomics Laboratory, Department of Biological Science and Engineering, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India
| | - Karthik Kalidoss
- Metabolomics and Proteomics Laboratory, Department of Biological Science and Engineering, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India
| | - Poonam Kumari Pathak
- Metabolomics and Proteomics Laboratory, Department of Biological Science and Engineering, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India
| | - Rahul Shrivastava
- Metabolomics and Proteomics Laboratory, Department of Biological Science and Engineering, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India.
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Dong J, Gong Z, Bi H, Yang J, Wang B, Du K, Zhang C, Chen L. BMSC-derived exosomal miR-219-5p alleviates ferroptosis in neuronal cells caused by spinal cord injury via the UBE2Z/NRF2 pathway. Neuroscience 2024; 556:73-85. [PMID: 39084457 DOI: 10.1016/j.neuroscience.2024.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 06/05/2024] [Accepted: 06/15/2024] [Indexed: 08/02/2024]
Abstract
OBJECTIVE The aim of this study was to investigate the molecular mechanism of exosomal miR-219-5p derived from bone marrow mesenchymal stem cells (BMSCs) in the treatment of spinal cord injury (SCI). METHODS Basso Beattie Bresnahan (BBB) score and tissue staining were used to assess SCI and neuronal survival in rats. The contents of Fe2+, malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were detected by a kit. The expression levels of ubiquitin-conjugating enzyme E2 Z (UBE2Z), nuclear factor erythroid 2-related Factor 2 (NRF2) and ferroptosis-related proteins were detected by Western blotting. In addition, the ability of BMSC-derived exosomes to inhibit ferroptosis in neuronal cells in rats with SCI was validated by in vivo injection of ferroptosis inhibitors/inducers. RESULTS In this study, we found that miR-219-5p-rich BMSC-derived exosomes inhibited ferroptosis in SCI rats and that the alleviating effect of BMSC-Exos on SCI was achieved by inhibiting the ferroptosis signaling pathway and that NRF2 played a key role in this process. Our study confirmed that BMSC exosome-specific delivery of miR-219-5p can target UBE2Z to regulate its stability and that overexpression of UBE2Z reverses miR-219-5p regulation of NRF2. In addition, in vivo experiments showed that BMSC exosomes alleviated ferroptosis in neuronal SCI progression, and inhibiting the expression of miR-219-5p in BMSCs reduced the alleviating effect of exosomes on ferroptosis in neuronal cells and SCI. CONCLUSION miR-219-5p in BMSC-derived exosomes can repair the injured spinal cord. In addition, miR-219-5p alleviates ferroptosis in neuronal cells induced by SCI through the UBE2Z/NRF2 pathway.
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Affiliation(s)
- Junjie Dong
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Zhiqiang Gong
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Hangchuan Bi
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Jin Yang
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Bing Wang
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Kaili Du
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Chunqiang Zhang
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Lingqiang Chen
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China.
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Zuo WF, Pang Q, Zhu X, Yang QQ, Zhao Q, He G, Han B, Huang W. Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies. J Hematol Oncol 2024; 17:81. [PMID: 39232809 PMCID: PMC11375894 DOI: 10.1186/s13045-024-01601-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 08/20/2024] [Indexed: 09/06/2024] Open
Abstract
Heat shock proteins are essential molecular chaperones that play crucial roles in stabilizing protein structures, facilitating the repair or degradation of damaged proteins, and maintaining proteostasis and cellular functions. Extensive research has demonstrated that heat shock proteins are highly expressed in cancers and closely associated with tumorigenesis and progression. The "Hallmarks of Cancer" are the core features of cancer biology that collectively define a series of functional characteristics acquired by cells as they transition from a normal state to a state of tumor growth, including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enabled replicative immortality, the induction of angiogenesis, and the activation of invasion and metastasis. The pivotal roles of heat shock proteins in modulating the hallmarks of cancer through the activation or inhibition of various signaling pathways has been well documented. Therefore, this review provides an overview of the roles of heat shock proteins in vital biological processes from the perspective of the hallmarks of cancer and summarizes the small-molecule inhibitors that target heat shock proteins to regulate various cancer hallmarks. Moreover, we further discuss combination therapy strategies involving heat shock proteins and promising dual-target inhibitors to highlight the potential of targeting heat shock proteins for cancer treatment. In summary, this review highlights how targeting heat shock proteins could regulate the hallmarks of cancer, which will provide valuable information to better elucidate and understand the roles of heat shock proteins in oncology and the mechanisms of cancer occurrence and development and aid in the development of more efficacious and less toxic novel anticancer agents.
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Affiliation(s)
- Wei-Fang Zuo
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qiwen Pang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xinyu Zhu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qian-Qian Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qian Zhao
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Gu He
- Department of Dermatology and Venereology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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Na X, Li L, Liu D, He J, Zhang L, Zhou Y. Natural products targeting ferroptosis pathways in cancer therapy (Review). Oncol Rep 2024; 52:123. [PMID: 39054952 PMCID: PMC11292301 DOI: 10.3892/or.2024.8782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Ferroptosis inducers (FIN) have a key role in cancer therapy and provide novel and innovative treatment strategies. Although many researchers have performed FIN screening of synthetic compounds, studies on the identification of FIN from natural products are limited, particularly in the field of drug development and combination therapy. In this review, this gap was addressed by comprehensively summarizing recent studies on ferroptosis. The causes of ferroptosis were categorized into driving and defensive factors, elucidating key pathways and targets. Next, through summarizing research on natural products that induce ferroptosis, the study elaborated in detail on the natural products that have FIN functions. Their discovery and development were also described and insight for clinical drug development was provided. In addition, the mechanisms of action were analyzed and potential combination therapies, resistance reversal and structural enhancements were presented. By highlighting the potential of natural products in inducing ferroptosis for cancer treatment, this review may serve as a reference for utilizing these compounds against cancer. It not only showed the significance of natural products but may also promote further investigation into their therapeutic effects, thus encouraging research in this field.
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Affiliation(s)
- Xin Na
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Lin Li
- Yunnan Cancer Hospital (Third Affiliated Hospital of Kunming Medical University), Kunming, Yunnan 650118, P.R. China
| | - Dongmei Liu
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Jiaqi He
- The First Clinical Medical College of Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Ling Zhang
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Yiping Zhou
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
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Li X, Yang X, Guo W, Li H, Sun W, Lin X, Ma Z, Li X, Liu Z. Natural products as inhibitors against pancreatic cancer cell proliferation and invasion: possible mechanisms. Am J Cancer Res 2024; 14:2695-2713. [PMID: 39005683 PMCID: PMC11236794 DOI: 10.62347/xlzx8935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 05/24/2024] [Indexed: 07/16/2024] Open
Abstract
Pancreatic cancer is one of the gastrointestinal tumors with the lowest survival rate and the worst prognosis. At the time of diagnosis, the majority of patients have missed the opportunity for radical surgical resection and opt for chemotherapy as their primary treatment choice. And drug resistance emerges during the application of the most widely used chemotherapeutic regimens such as modified FOLFIRINOX regimen, gemcitabine monotherapy or 5-Fluorouracil combination therapy, which further reduces the therapeutic efficacy. Therefore, it is urgent to explore better treatment strategies for pancreatic cancer. In recent years, more and more studies have found that natural products have significant anti-pancreatic cancer properties. In this paper, we reviewed the possible mechanisms by which natural products inhibit the proliferation and invasion of pancreatic cancer cells, including the possible mechanisms of targeting the inhibition of the growth and proliferation regulatory pathways of pancreatic cancer cells, inducing apoptosis and autophagy of pancreatic cancer cells, inhibiting the EMT process of pancreatic cancer cells, and inhibiting the angiogenesis of pancreatic cancer. Meanwhile, natural products have also hindered the progress of their basic and clinical research due to the complexity of their composition and the limitation of biological extraction technology. Further exploration of the specific molecular mechanisms of natural products to inhibit the proliferation and invasion of pancreatic cancer cells, optimization of purification and preparation techniques, and enrichment of basic and clinical trials to verify their efficacy and safety may be the future direction of natural products in the field of anti-pancreatic cancer research.
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Affiliation(s)
- Xiang Li
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
| | - Xu Yang
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
| | - Wei Guo
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
| | - Hao Li
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
| | - Weiqing Sun
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
| | - Xingda Lin
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
| | - Zuoxin Ma
- Medical Laboratory, Liaoning Province Hospital Shenyang 110001, Liaoning, China
| | - Xuan Li
- Department of Orthopedics, Liaoning Province Hospital Shenyang 110001, Liaoning, China
| | - Zhe Liu
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
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Wang Z, Wu D, Zhang Y, Chen W, Yang Y, Yang Y, Zu G, An Y, Yu X, Qin Y, Xu X, Chen X. PITX2 functions as a transcription factor for GPX4 and protects pancreatic cancer cells from ferroptosis. Exp Cell Res 2024; 439:114074. [PMID: 38710403 DOI: 10.1016/j.yexcr.2024.114074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 04/21/2024] [Accepted: 05/02/2024] [Indexed: 05/08/2024]
Abstract
Ferroptosis inhibits tumor progression in pancreatic cancer cells, while PITX2 is known to function as a pro-oncogenic factor in various tumor types, protecting them from ferroptosis and thereby promoting tumor progression. In this study, we sought to investigate the regulatory role of PITX2 in tumor cell ferroptosis within the context of pancreatic cancer. We conducted PITX2 knockdown experiments using lentiviral infection in two pancreatic cancer cell lines, namely PANC-1 and BxPC-3. We assessed protein expression through immunoblotting and mRNA expression through RT-PCR. To confirm PITX2 as a transcription factor for GPX4, we employed Chromatin Immunoprecipitation (ChIP) and Dual-luciferase assays. Furthermore, we used flow cytometry to measure reactive oxygen species (ROS), lipid peroxidation, and apoptosis and employed confocal microscopy to assess mitochondrial membrane potential. Additionally, electron microscopy was used to observe mitochondrial structural changes and evaluate PITX2's regulation of ferroptosis in pancreatic cancer cells. Our findings demonstrated that PITX2, functioning as a transcription factor for GPX4, promoted GPX4 expression, thereby exerting an inhibitory effect on ferroptosis in pancreatic cancer cells and consequently promoting tumor progression. Moreover, PITX2 enhanced the invasive and migratory capabilities of pancreatic cancer cells by activating the WNT signaling pathway. Knockdown of PITX2 increased ferroptosis and inhibited the proliferation of PANC-1 and BxPC-3 cells. Notably, the inhibitory effect on ferroptosis resulting from PITX2 overexpression in these cells could be countered using RSL3, an inhibitor of GPX4. Overall, our study established PITX2 as a transcriptional regulator of GPX4 that could promote tumor progression in pancreatic cancer by reducing ferroptosis. These findings suggest that PITX2 may serve as a potential therapeutic target for combating ferroptosis in pancreatic cancer.
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Affiliation(s)
- Zhiliang Wang
- Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Di Wu
- Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Yue Zhang
- Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Weibo Chen
- Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Yang Yang
- Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Yue Yang
- Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Guangchen Zu
- Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Yong An
- Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Department of Oncology, Shanghai Medical College, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Department of Oncology, Shanghai Medical College, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Xiaowu Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Department of Oncology, Shanghai Medical College, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Xuemin Chen
- Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
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10
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Xia Y, Tang Y, Huang Z, Ke N, Zheng Y, Zhuang W, Zhang Y, Yin X, Tu M, Chen J, Wang Y, Huang Y. Artesunate-loaded solid lipid nanoparticles resist esophageal squamous cell carcinoma by inducing Ferroptosis through inhibiting the AKT/mTOR signaling. Cell Signal 2024; 117:111108. [PMID: 38369266 DOI: 10.1016/j.cellsig.2024.111108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 02/02/2024] [Accepted: 02/15/2024] [Indexed: 02/20/2024]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a severe malignancy with high incidence and mortality rate in China, while the application of standard chemotherapeutic drugs for ESCC meets the barriers of high toxicity and multiple drug resistance (MDR). In recent years, the anticancer effects of artesunate (ART), a Chinese medicine monomer have gained extensive attentions due to its characteristics of low toxicity, high potency, and reversal of MDR. In this study, we develop the artesunate-loaded solid lipid nanoparticles (SLNART) to overcome the poor water solubility and bioavailability of ART, further improving the efficiency of ART on ESCC treatment. Especially mentioned, SLNART is shown to present marked inhibitory effects on ESCC development based on the induction of ferroptosis by two pathways included upregulating TFR to increase Fe2+ ions and inhibiting the AKT/mTOR signaling to downregulate GPX4. Collectively, this study is the first to pave a promising approach for ESCC therapy based on a strategy of developing SLNART to induce ferroptosis by mediating Fe2+ ions and AKT/mTOR signaling.
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Affiliation(s)
- Yu Xia
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China; Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou 350001, China
| | - Yixin Tang
- College of Chemical Engineering, Fuzhou University, Fuzhou 350108, China; Engineering Research Center of Advanced Manufacturing Technology for Fine Chemicals, College of Chemical Engineering, Fuzhou University, Fuzhou 350108, China
| | - Zhixin Huang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China; Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou 350001, China
| | - Nantian Ke
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; Department of Clinical Laboratory, Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou 350001, China
| | - Yue Zheng
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou 350001, China; Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China
| | - Wanzhen Zhuang
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou 350001, China; Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China
| | - Yi Zhang
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou 350001, China; Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China
| | - Xiaoqing Yin
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China; Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou 350001, China
| | - Mingshu Tu
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou 350001, China; Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China
| | - Jianlin Chen
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou 350001, China; Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China
| | - Yingshu Wang
- College of Chemical Engineering, Fuzhou University, Fuzhou 350108, China; Engineering Research Center of Advanced Manufacturing Technology for Fine Chemicals, College of Chemical Engineering, Fuzhou University, Fuzhou 350108, China
| | - Yi Huang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China; Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou 350001, China; Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; Central Laboratory, Center for Experimental Research in Clinical Medicine, Fujian Provincial Hospital, Fuzhou 350001, China; Fujian Provincial Key Laboratory of Critical Care Medicine, Fujian Provincial Key Laboratory of Cardiovascular Disease, Fuzhou 350001, China.
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11
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Wang Y, Yuan X, Ren M, Wang Z. Ferroptosis: A New Research Direction of Artemisinin and Its Derivatives in Anti-Cancer Treatment. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:161-181. [PMID: 38328829 DOI: 10.1142/s0192415x24500071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Ferroptosis, an iron-dependent cell death mechanism driven by an accumulation of lipid peroxides on cellular membranes, has emerged as a promising strategy to treat various diseases, including cancer. Ferroptosis inducers not only exhibit cytotoxic effects on multiple cancer cells, including drug-resistant cancer variants, but also hold potential as adjuncts to enhance the efficacy of other anti-cancer therapies, such as immunotherapy. In addition to synthetic inducers, natural compounds, such as artemisinin, can be considered ferroptosis inducers. Artemisinin, extracted from Artemisia annua L., is a poorly water-soluble antimalarial drug. For clinical applications, researchers have synthesized various water-soluble artemisinin derivatives such as dihydroartemisinin, artesunate, and artemether. Artemisinin and artemisinin derivatives (ARTEs) upregulate intracellular free iron levels and promote the accumulation of intracellular lipid peroxides to induce cancer cell ferroptosis, alleviating cancer development and resulting in strong anti-cancer effects in vitro and in vivo. In this review, we introduce the mechanisms of ferroptosis, summarize the research on ARTEs-induced ferroptosis in cancer cells, and discuss the clinical research progress and current challenges of ARTEs in anti-cancer treatment. This review deepens the current understanding of the relationship between ARTEs and ferroptosis and provides a theoretical basis for the clinical anti-cancer application of ARTEs in the future.
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Affiliation(s)
- Youke Wang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, P. R. China
- Guangdong Provincial Key Laboratory of Clinical, Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510006, Guangdong, P. R. China
| | - Xiang Yuan
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, P. R. China
| | - Min Ren
- Abdominal Oncology Ward, Division of Radiation Oncology, Cancer Center West China Hospital, Sichuan University, Chengdu 610041 Sichuan, P. R. China
| | - Zhiyu Wang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China
- Guangdong Provincial Key Laboratory of Clinical, Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510006, Guangdong, P. R. China
- Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, P. R. China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, P. R. China
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12
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Xiao Q, Lan Z, Zhang S, Ren H, Wang S, Wang P, Feng L, Li D, Wang C, Bai X, Zhang J. Overexpression of ZNF488 supports pancreatic cancer cell proliferation and tumorigenesis through inhibition of ferroptosis via regulating SCD1-mediated unsaturated fatty acid metabolism. Biol Direct 2023; 18:77. [PMID: 37986084 PMCID: PMC10658979 DOI: 10.1186/s13062-023-00421-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 10/02/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Pancreatic cancer is a malignancy with high mortality. Once diagnosed, effective treatment strategies are limited and the five-year survival is extremely poor. Recent studies have shown that zinc finger proteins play important roles in tumorigenesis, including pancreatic cancer. However, it remains unknown on the clinical significance, function and underlying mechanisms of zinc finger protein 488 (ZNF488) during the development of pancreatic cancer. METHODS The clinical relevance of ZNF488 and stearoyl-CoA desaturase 1 (SCD1) was examined by analyzing the data from The Cancer Genome Atlas (TCGA) and immunohistochemical staining of the tissue microarray. Gain-of-function and loss-of-function experiments were performed by transfecting the cells with overexpressing lentivirus and siRNAs or shRNA lentivirus, respectively. The function of ZNF488 in pancreatic cancer was assessed by CCK8, colony formation, EdU staining, PI/Annexin V staining and xenografted tumorigenesis. Chip-qPCR assay was conducted to examine the interaction between ZNF488 and the promoter sequence of SCD1. Transcription activity was measured by dual luciferase reporter assay. mRNA and protein expression was detected by qRT-PCR and immunoblotting experiment, respectively. Fatty acid was quantified by gas chromatography mass spectrometry. RESULTS ZNF488 was overexpressed in pancreatic cancer samples compared with normal tissues. High expression of ZNF488 predicted the poor prognosis of the patients. In vitro, ZNF488 upregulation contributed to the EuU cooperation, proliferation and colony formation of MIAPaCa-2 and PANC-1 cells. Based on PI/Annexin V and trypan blue staining results, we showed that ZNF488 suppressed the ferroptosis and apoptosis of pancreatic cancer cells. Mechanistically, ZNF488 directly interacted with the promoter sequence of SCD1 gene and promoted its transcription activity, which resulted in enhanced palmitoleic and oleic acid production, as well as the peroxidation of fatty acid. In vivo, ZNF488 overexpression promoted the xenograted tumorigenesis of PANC-1, which was reversed by SCD1 knockdown. Importantly, combination of erastin and SCD1 inhibitors A939572 completely blunted the growth of ZNF488 overexpressed MIAPaCa-2 and PANC-1 cells. Usage of A939572 or erastin recovered the sensitivity of pancreatic cancer cells to the treatment of gemcitabine. Lastly, we found a positive correlation between ZNF488 and SCD1 in pancreatic cancer patients based on TCGA and immunohistochemical staining results. CONCLUSION Overexpression of ZNF488 suppresses the ferroptosis and apoptosis to support the growth and tumorigenesis of pancreatic cancer through augmentation of SCD1-mediated unsaturated fatty acid metabolism. Combination of SCD1 inhibitors, ferroptosis inducers or gemcitabine could be applied for the treatment of pancreatic cancer with overexpression of ZNF488.
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Affiliation(s)
- Qifeng Xiao
- Pancreatic and gastric surgery department, National Cancer Center/National clinical research center for cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhongmin Lan
- Pancreatic and gastric surgery department, National Cancer Center/National clinical research center for cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shuisheng Zhang
- Pancreatic and gastric surgery department, National Cancer Center/National clinical research center for cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hu Ren
- Pancreatic and gastric surgery department, National Cancer Center/National clinical research center for cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shunda Wang
- Pancreatic and gastric surgery department, National Cancer Center/National clinical research center for cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Peng Wang
- Pancreatic and gastric surgery department, National Cancer Center/National clinical research center for cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lin Feng
- State Key Laboratory of Molecular Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Dan Li
- State Key Laboratory of Molecular Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chengfeng Wang
- Pancreatic and gastric surgery department, National Cancer Center/National clinical research center for cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiaofeng Bai
- Pancreatic and gastric surgery department, National Cancer Center/National clinical research center for cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jianwei Zhang
- Pancreatic and gastric surgery department, National Cancer Center/National clinical research center for cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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13
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Zhang JB, Jia X, Cao Q, Chen YT, Tong J, Lu GD, Li DJ, Han T, Zhuang CL, Wang P. Ferroptosis-Regulated Cell Death as a Therapeutic Strategy for Neurodegenerative Diseases: Current Status and Future Prospects. ACS Chem Neurosci 2023; 14:2995-3012. [PMID: 37579022 DOI: 10.1021/acschemneuro.3c00406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/16/2023] Open
Abstract
Ferroptosis is increasingly being recognized as a key element in the pathogenesis of diverse diseases. Recent studies have highlighted the intricate links between iron metabolism and neurodegenerative disorders. Emerging evidence suggests that iron homeostasis, oxidative stress, and neuroinflammation all contribute to the regulation of both ferroptosis and neuronal health. However, the precise molecular mechanisms underlying the involvement of ferroptosis in the pathological processes of neurodegeneration and its impact on neuronal dysfunction remain incompletely understood. In our Review, we provide a comprehensive analysis and summary of the potential molecular mechanisms underlying ferroptosis in neurodegenerative diseases, aiming to elucidate the disease progression of neurodegeneration. Additionally, we discuss potential therapeutic agents that modulate ferroptosis with the goal of identifying novel drug molecules for the treatment of neurodegenerative disorders.
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Affiliation(s)
- Jia-Bao Zhang
- Department of Pharmacology, College of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
- National Experimental Teaching Demonstration Center of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
| | - Xiuqin Jia
- Department of Radiology, Beijing Chao Yang Hospital, Capital Medical University, Chaoyang District, Beijing 100020, China
| | - Qi Cao
- Department of Pharmacology, College of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
- National Experimental Teaching Demonstration Center of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
| | - Yi-Ting Chen
- Department of Pharmacology, College of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
| | - Jie Tong
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Guo-Dong Lu
- Department of Pharmacology, College of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
| | - Dong-Jie Li
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ting Han
- Department of Pharmacology, College of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
| | - Chun-Lin Zhuang
- Department of Pharmacology, College of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
| | - Pei Wang
- Department of Pharmacology, College of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
- National Experimental Teaching Demonstration Center of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
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14
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Shan C, Liang Y, Wang K, Li P. Noncoding RNAs in cancer ferroptosis: From biology to clinical opportunity. Biomed Pharmacother 2023; 165:115053. [PMID: 37379641 DOI: 10.1016/j.biopha.2023.115053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/16/2023] [Accepted: 06/21/2023] [Indexed: 06/30/2023] Open
Abstract
Ferroptosis is a recently discovered pattern of programmed cell death that is nonapoptotic and irondependent. It is involved in lipid peroxidation dependent on reactive oxygen species. Ferroptosis has been verified to play a crucial regulatory role in a variety of pathological courses of disease, in particularly cancer. Emerging research has highlighted the potential of ferroptosis in tumorigenesis, cancer development and resistance to chemotherapy. However, the regulatory mechanism of ferroptosis remains unclear, which limits the application of ferroptosis in cancer treatment. Noncoding RNAs (ncRNAs) are noncoding transcripts that regulate gene expression in various ways to affect the malignant phenotypes of cancer cells. At present, the biological function and underlying regulatory mechanism of ncRNAs in cancer ferroptosis have been partially elucidated. Herein, we summarize the current knowledge of the central regulatory network of ferroptosis, with a focus on the regulatory functions of ncRNAs in cancer ferroptosis. The clinical application and prospects of ferroptosis-related ncRNAs in cancer diagnosis, prognosis and anticancer therapies are also discussed. Elucidating the function and mechanism of ncRNAs in ferroptosis, along with assessing the clinical significance of ferroptosis-related ncRNAs, provides new perspectives for understanding cancer biology and treatment approaches, which may benefit numerous cancer patients in the future.
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Affiliation(s)
- Chan Shan
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
| | - Yan Liang
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China
| | - Kun Wang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Peifeng Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
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15
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Li L, Lu P, Liu Y, Yang J, Li S. Three-Dimensional-Bioprinted Bioactive Glass/Cellulose Composite Scaffolds with Porous Structure towards Bone Tissue Engineering. Polymers (Basel) 2023; 15:polym15092226. [PMID: 37177373 PMCID: PMC10180722 DOI: 10.3390/polym15092226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 04/28/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023] Open
Abstract
In this study, three-dimensional (3D) bioactive glass/lignocellulose (BG/cellulose) composite scaffolds were successfully fabricated by the 3D-bioprinting technique with N-methylmorpholine-N-oxide (NMMO) as the ink solvent. The physical structure, morphology, mechanical properties, hydroxyapatite growth and cell response to the prepared BG/cellulose scaffolds were investigated. Scanning electron microscopy (SEM) images showed that the BG/cellulose scaffolds had uniform macropores of less than 400 μm with very rough surfaces. Such BG/cellulose scaffolds have excellent mechanical performance to resist compressive force in comparison with pure cellulose scaffolds and satisfy the strength requirement of human trabecular bone (2-12 MPa). Furthermore, BG significantly increased the excellent hydroxyapatite-forming capability of the cellulose scaffolds as indicated by the mineralization of the scaffolds in simulated body fluid (SBF). The BG/cellulose scaffolds showed low cytotoxicity to human bone marrow mesenchymal stem cells (hBMSCs) in the CCK8 assay. The cell viability reached maximum (percent of the control group) when the weight ratio of cellulose to BG was 2 in the scaffold. Therefore, the 3D-printed BG/cellulose scaffolds show a potential application in the field of bone tissue engineering.
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Affiliation(s)
- Lei Li
- School of Materials and Chemistry, University of Shanghai for Science and Technology, 516 Jungong Road, Shanghai 200093, China
| | - Pengfei Lu
- School of Materials and Chemistry, University of Shanghai for Science and Technology, 516 Jungong Road, Shanghai 200093, China
| | - Yuting Liu
- School of Materials and Chemistry, University of Shanghai for Science and Technology, 516 Jungong Road, Shanghai 200093, China
| | - Junhe Yang
- School of Materials and Chemistry, University of Shanghai for Science and Technology, 516 Jungong Road, Shanghai 200093, China
| | - Shengjuan Li
- School of Materials and Chemistry, University of Shanghai for Science and Technology, 516 Jungong Road, Shanghai 200093, China
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16
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Zhang R, Kang R, Tang D. Ferroptosis in gastrointestinal cancer: From mechanisms to implications. Cancer Lett 2023; 561:216147. [PMID: 36965540 DOI: 10.1016/j.canlet.2023.216147] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/16/2023] [Accepted: 03/22/2023] [Indexed: 03/27/2023]
Abstract
Ferroptosis is a form of regulated cell death that is initiated by excessive lipid peroxidation that results in plasma membrane damage and the release of damage-associated molecular patterns. In recent years, ferroptosis has gained significant attention in cancer research due to its unique mechanism compared to other forms of regulated cell death, especially caspase-dependent apoptotic cell death. Gastrointestinal (GI) cancer encompasses malignancies that arise in the digestive tract, including the stomach, intestines, pancreas, colon, liver, rectum, anus, and biliary system. These cancers are a global health concern, with high incidence and mortality rates. Despite advances in medical treatments, drug resistance caused by defects in apoptotic pathways remains a persistent challenge in the management of GI cancer. Hence, exploring the role of ferroptosis in GI cancers may lead to more efficacious treatment strategies. In this review, we provide a comprehensive overview of the core mechanism of ferroptosis and discuss its function, regulation, and implications in the context of GI cancers.
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Affiliation(s)
- Ruoxi Zhang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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17
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Pan W, Jie W, Huang H. Vascular calcification: Molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2023; 4:e200. [PMID: 36620697 PMCID: PMC9811665 DOI: 10.1002/mco2.200] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 01/05/2023] Open
Abstract
Vascular calcification (VC) is recognized as a pathological vascular disorder associated with various diseases, such as atherosclerosis, hypertension, aortic valve stenosis, coronary artery disease, diabetes mellitus, as well as chronic kidney disease. Therefore, it is a life-threatening state for human health. There were several studies targeting mechanisms of VC that revealed the importance of vascular smooth muscle cells transdifferentiating, phosphorous and calcium milieu, as well as matrix vesicles on the progress of VC. However, the underlying molecular mechanisms of VC need to be elucidated. Though there is no acknowledged effective therapeutic strategy to reverse or cure VC clinically, recent evidence has proved that VC is not a passive irreversible comorbidity but an active process regulated by many factors. Some available approaches targeting the underlying molecular mechanism provide promising prospects for the therapy of VC. This review aims to summarize the novel findings on molecular mechanisms and therapeutic interventions of VC, including the role of inflammatory responses, endoplasmic reticulum stress, mitochondrial dysfunction, iron homeostasis, metabolic imbalance, and some related signaling pathways on VC progression. We also conclude some recent studies on controversial interventions in the clinical practice of VC, such as calcium channel blockers, renin-angiotensin system inhibitions, statins, bisphosphonates, denosumab, vitamins, and ion conditioning agents.
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Affiliation(s)
- Wei Pan
- Department of Cardiology, the Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhenGuangdongChina
- Joint Laboratory of Guangdong‐Hong Kong‐Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic DiseaseSun Yat‐sen UniversityShenzhenGuangdongChina
| | - Wei Jie
- Department of Cardiology, the Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhenGuangdongChina
- Joint Laboratory of Guangdong‐Hong Kong‐Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic DiseaseSun Yat‐sen UniversityShenzhenGuangdongChina
| | - Hui Huang
- Department of Cardiology, the Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhenGuangdongChina
- Joint Laboratory of Guangdong‐Hong Kong‐Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic DiseaseSun Yat‐sen UniversityShenzhenGuangdongChina
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18
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Resolution Potential of Necrotic Cell Death Pathways. Int J Mol Sci 2022; 24:ijms24010016. [PMID: 36613458 PMCID: PMC9819908 DOI: 10.3390/ijms24010016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
During tissue damage caused by infection or sterile inflammation, not only damage-associated molecular patterns (DAMPs), but also resolution-associated molecular patterns (RAMPs) can be activated. These dying cell-associated factors stimulate immune cells localized in the tissue environment and induce the production of inflammatory mediators or specialized proresolving mediators (SPMs). Within the current prospect of science, apoptotic cell death is considered the main initiator of resolution. However, more RAMPs are likely to be released during necrotic cell death than during apoptosis, similar to what has been observed for DAMPs. The inflammatory potential of many regulated forms of necrotic cell death modalities, such as pyroptosis, necroptosis, ferroptosis, netosis, and parthanatos, have been widely studied in necroinflammation, but their possible role in resolution is less considered. In this review, we aim to summarize the relationship between necrotic cell death and resolution, as well as present the current available data regarding the involvement of certain forms of regulated necrotic cell death in necroresolution.
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19
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Gastric Cancer Cell-Derived Exosomal GRP78 Enhances Angiogenesis upon Stimulation of Vascular Endothelial Cells. Curr Issues Mol Biol 2022; 44:6145-6157. [PMID: 36547080 PMCID: PMC9776843 DOI: 10.3390/cimb44120419] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/03/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022] Open
Abstract
Exosomes containing glucose-regulated protein 78 (GRP78) are involved in cancer malignancy. GRP78 is thought to promote the tumor microenvironment, leading to angiogenesis. No direct evidence for this role has been reported, however, mainly because of difficulties in accurately measuring the GRP78 concentration in the exosomes. Recently, exosomal GRP78 concentrations were successfully measured using an ultrasensitive ELISA. In the present study, GRP78 concentrations in exosomes collected from gastric cancer AGS cells with overexpression of GRP78 (OE), knockdown of GRP78 (KD), or mock GRP78 (mock) were quantified. These three types of exosomes were then incubated with vascular endothelial cells to examine their effects on endothelial cell angiogenesis. Based on the results of a tube formation assay, GRP78-OE exosomes accelerated angiogenesis compared with GRP78-KD or GRP78-mock exosomes. To investigate the mechanisms underlying this effect, we examined the Ser473 phosphorylation state ratio of AKT, which is involved in the angiogenesis process, and found that AKT phosphorylation was increased by GRP78-OE exosome application to the endothelial cells. An MTT assay showed that GRP78-OE exosome treatment increased the proliferation rate of endothelial cells, and a wound healing assay showed that this treatment increased the migration capacity of the endothelial cells. These findings demonstrated that GRP78-containing exosomes promote the tumor microenvironment and induce angiogenesis.
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20
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Yin L, Liu P, Jin Y, Ning Z, Yang Y, Gao H. Ferroptosis-related small-molecule compounds in cancer therapy: Strategies and applications. Eur J Med Chem 2022; 244:114861. [DOI: 10.1016/j.ejmech.2022.114861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/07/2022] [Accepted: 10/17/2022] [Indexed: 01/17/2023]
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21
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Yin X, Xu R, Song J, Ruze R, Chen Y, Wang C, Xu Q. Lipid metabolism in pancreatic cancer: emerging roles and potential targets. CANCER COMMUNICATIONS (LONDON, ENGLAND) 2022; 42:1234-1256. [PMID: 36107801 PMCID: PMC9759769 DOI: 10.1002/cac2.12360] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 07/05/2022] [Accepted: 08/05/2022] [Indexed: 01/25/2023]
Abstract
Pancreatic cancer is one of the most serious health issues in developed and developing countries, with a 5-year overall survival rate currently <9%. Patients typically present with advanced disease due to vague symptoms or lack of screening for early cancer detection. Surgical resection represents the only chance for cure, but treatment options are limited for advanced diseases, such as distant metastatic or locally progressive tumors. Although adjuvant chemotherapy has improved long-term outcomes in advanced cancer patients, its response rate is low. So, exploring other new treatments is urgent. In recent years, increasing evidence has shown that lipid metabolism can support tumorigenesis and disease progression as well as treatment resistance through enhanced lipid synthesis, storage, and catabolism. Therefore, a better understanding of lipid metabolism networks may provide novel and promising strategies for early diagnosis, prognosis estimation, and targeted therapy for pancreatic cancer patients. In this review, we first enumerate and discuss current knowledge about the advances made in understanding the regulation of lipid metabolism in pancreatic cancer. In addition, we summarize preclinical studies and clinical trials with drugs targeting lipid metabolic systems in pancreatic cancer. Finally, we highlight the challenges and opportunities for targeting lipid metabolism pathways through precision therapies in pancreatic cancer.
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Affiliation(s)
- Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
| | - Jianlu Song
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
| | - Rexiati Ruze
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
| | - Chengcheng Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
| | - Qiang Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
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22
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Identification of novel prognostic risk signature of breast cancer based on ferroptosis-related genes. Sci Rep 2022; 12:13766. [PMID: 35962042 PMCID: PMC9374692 DOI: 10.1038/s41598-022-18044-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 08/04/2022] [Indexed: 12/05/2022] Open
Abstract
Ferroptosis is a type of cell regulated necrosis triggered by intracellular phospholipid peroxidation, which is more immunogenic than apoptosis. Therefore, genes controlling ferroptosis may be promising candidate biomarkers for tumor therapy. In this study, we investigate the function of genes associated with ferroptosis in breast cancer (BC) and systematically evaluate the relationship between ferroptosis-related gene expression and prognosis of BC patients from the Cancer Genome Atlas database. By using the consensus clustering method, 1203 breast cancer samples were clustered into two clearly divided subgroups based on the expression of 237 ferroptosis-related genes. Then differentially expressed analysis and least absolute shrinkage and selection operator were used to identify the prognosis-related genes. Furthermore, the genetic risk signature was constructed using the expression of prognosis-related genes. Our results showed that the genetic risk signature can identify patient subgroups with distinct prognosis in either training cohort or validation, and the genetic risk signature was associated with the tumor immune microenvironment. Finally, the Cox regression analysis indicated that our risk signature was an independent prognostic factor for BC patients and this signature was verified by the polymerase chain reaction and western blot. Within this study, we identified a novel prognostic classifier based on five ferroptosis-related genes which may provide a new reference for the treatment of BRCA patients.
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Andreani C, Bartolacci C, Scaglioni PP. Ferroptosis: A Specific Vulnerability of RAS-Driven Cancers? Front Oncol 2022; 12:923915. [PMID: 35912247 PMCID: PMC9337859 DOI: 10.3389/fonc.2022.923915] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 05/03/2022] [Indexed: 12/11/2022] Open
Abstract
Ferroptosis has emerged as a new type of programmed cell death that can be harnessed for cancer therapy. The concept of ferroptosis was for the first time proposed in in the early 2000s, as an iron-dependent mode of regulated cell death caused by unrestricted lipid peroxidation (LPO) and subsequent plasma membrane rupture. Since the discovery and characterization of ferroptosis, a wealth of research has improved our understanding of the main pathways regulating this process, leading to both the repurposing and the development of small molecules. However, ferroptosis is still little understood and several aspects remain to be investigated. For instance, it is unclear whether specific oncogenes, cells of origin or tumor niches impose specific susceptibility/resistance to ferroptosis or if there are some ferroptosis-related genes that may be used as bona fide pan-cancer targetable dependencies. In this context, even though RAS-driven cancer cell lines seemed to be selectively sensitive to ferroptosis inducers, subsequent studies have questioned these results, indicating that in some cases mutant RAS is necessary, but not sufficient to induce ferroptosis. In this perspective, based on publicly available genomic screening data and the literature, we discuss the relationship between RAS-mutation and ferroptosis susceptibility in cancer.
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Affiliation(s)
| | | | - Pier Paolo Scaglioni
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Ferroptosis and Its Role in Chronic Diseases. Cells 2022; 11:cells11132040. [PMID: 35805124 PMCID: PMC9265893 DOI: 10.3390/cells11132040] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/23/2022] [Accepted: 06/25/2022] [Indexed: 02/04/2023] Open
Abstract
Ferroptosis, which has been widely associated with many diseases, is an iron-dependent regulated cell death characterized by intracellular lipid peroxide accumulation. It exhibits morphological, biochemical, and genetic characteristics that are unique in comparison to other types of cell death. The course of ferroptosis can be accurately regulated by the metabolism of iron, lipids, amino acids, and various signal pathways. In this review, we summarize the basic characteristics of ferroptosis, its regulation, as well as the relationship between ferroptosis and chronic diseases such as cancer, nervous system diseases, metabolic diseases, and inflammatory bowel diseases. Finally, we describe the regulatory effects of food-borne active ingredients on ferroptosis.
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25
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Laurella LC, Mirakian NT, Garcia MN, Grasso DH, Sülsen VP, Papademetrio DL. Sesquiterpene Lactones as Promising Candidates for Cancer Therapy: Focus on Pancreatic Cancer. Molecules 2022; 27:3492. [PMID: 35684434 PMCID: PMC9182036 DOI: 10.3390/molecules27113492] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/24/2022] [Accepted: 05/24/2022] [Indexed: 11/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease which confers to patients a poor prognosis at short term. PDAC is the fourth leading cause of death among cancers in the Western world. The rate of new cases of pancreatic cancer (incidence) is 10 per 100,000 but present a 5-year survival of less than 10%, highlighting the poor prognosis of this pathology. Furthermore, 90% of advanced PDAC tumor present KRAS mutations impacting in several oncogenic signaling pathways, many of them associated with cell proliferation and tumor progression. Different combinations of chemotherapeutic agents have been tested over the years without an improvement of significance in its treatment. PDAC remains as one the more challenging biomedical topics thus far. The lack of a proper early diagnosis, the notable mortality statistics and the poor outcome with the available therapies urge the entire scientific community to find novel approaches against PDAC with real improvements in patients' survival and life quality. Natural compounds have played an important role in the process of discovery and development of new drugs. Among them, terpenoids, such as sesquiterpene lactones, stand out due to their biological activities and pharmacological potential as antitumor agents. In this review, we will describe the sesquiterpene lactones with in vitro and in vivo activity against pancreatic tumor cells. We will also discuss the mechanism of action of the compounds as well as the signaling pathways associated with their activity.
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Affiliation(s)
- Laura Cecilia Laurella
- Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), CONICET-Universidad de Buenos Aires, Junín 956, Piso 2, Buenos Aires CP 1113, Argentina;
- Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires CP 1113, Argentina;
| | - Nadia Talin Mirakian
- Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires CP 1113, Argentina;
| | - Maria Noé Garcia
- Cátedra de Inmunología, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires CP 1113, Argentina;
- Instituto de Estudios de la Inmunidad Humoral (IDEHU), CONICET-Universidad de Buenos Aires, Junín 956, Piso 4, Buenos Aires CP 1113, Argentina;
| | - Daniel Héctor Grasso
- Instituto de Estudios de la Inmunidad Humoral (IDEHU), CONICET-Universidad de Buenos Aires, Junín 956, Piso 4, Buenos Aires CP 1113, Argentina;
- Cátedra de Fisiopatología, Departamento de Ciencias Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires CP 1113, Argentina
| | - Valeria Patricia Sülsen
- Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), CONICET-Universidad de Buenos Aires, Junín 956, Piso 2, Buenos Aires CP 1113, Argentina;
- Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires CP 1113, Argentina;
| | - Daniela Laura Papademetrio
- Cátedra de Inmunología, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires CP 1113, Argentina;
- Instituto de Estudios de la Inmunidad Humoral (IDEHU), CONICET-Universidad de Buenos Aires, Junín 956, Piso 4, Buenos Aires CP 1113, Argentina;
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Gong F, Ge T, Liu J, Xiao J, Wu X, Wang H, Zhu Y, Xia D, Hu B. Trehalose inhibits ferroptosis via NRF2/HO-1 pathway and promotes functional recovery in mice with spinal cord injury. Aging (Albany NY) 2022; 14:3216-3232. [PMID: 35400664 PMCID: PMC9037257 DOI: 10.18632/aging.204009] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/25/2022] [Indexed: 11/25/2022]
Abstract
Spinal cord injury (SCI) is the main cause of severe damage to the central nervous system and leads to irreversible tissue loss and neurological dysfunction. Ferroptosis is a cell death pattern, newly discovered in recent years. Ferroptosis is an oxidizing cell death induced by small molecules, and is an iron-dependent process caused by the imbalance between the generation and degradation of lipid reactive oxygen species (ROS) in cells. As an antioxidant, trehalose can effectively prevent lipid peroxidation. Studies have reported that trehalose can improve the prognosis of SCI. However, it is unclear whether these benefits are related to ferroptosis. In this study, we demonstrated for the first time that trehalose reduces the degeneration and iron accumulation of neurons by inhibiting the production of ROS and ferroptosis caused by lipid peroxides after SCI, thus promoting the survival of neurons and improving the recovery of motor function. More specifically, we found that trehalose inhibited the expansion of cavities in the nerve tissue of mice with SCI, inhibited neuron loss, and improved functional recovery. In terms of mechanism, our results indicate that the neuroprotective effect of trehalose is due to the activation of the NRF2/HO-1 pathway, which in turn inhibits ferroptosis and ferroptosis-related inflammation. Our findings provide important insights into the previously unknown role of trehalose in SCI, as well as new evidence supporting the hypothesis that suppression of ferroptosis plays a key neuroprotective role in SCI.
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Affiliation(s)
- Fangyi Gong
- Department of Orthopedics, Ningbo First Hospital, Ningbo, China
| | - Ting Ge
- Department of Orthopedics, Ningbo First Hospital, Ningbo, China
| | - Jing Liu
- Department of Emergency Medicine, Ningbo First Hospital, Ningbo, China
| | - Jin Xiao
- Department of Orthopedics, Ningbo First Hospital, Ningbo, China
| | - Xiaochuan Wu
- Department of Orthopedics, Ningbo First Hospital, Ningbo, China
| | - Hehui Wang
- Department of Orthopedics, Ningbo First Hospital, Ningbo, China
| | - Yingchun Zhu
- Department of Orthopedics, Ningbo First Hospital, Ningbo, China
| | - Dongdong Xia
- Department of Orthopedics, Ningbo First Hospital, Ningbo, China
| | - Baiwen Hu
- Department of Orthopedics, Ningbo First Hospital, Ningbo, China
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Hypoxia Enhances HIF1α Transcription Activity by Upregulating KDM4A and Mediating H3K9me3, Thus Inducing Ferroptosis Resistance in Cervical Cancer Cells. Stem Cells Int 2022; 2022:1608806. [PMID: 35287356 PMCID: PMC8917951 DOI: 10.1155/2022/1608806] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 01/06/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
Objective Cervical cancer (CC) is a prevalent cancer in women. Hypoxia plays a critical role in CC cell ferroptosis resistance. This study explored the mechanism of hypoxia in CC cell ferroptosis resistance by regulating HIF1α/KDM4A/H3K9me3. Methods Cultured SiHa and Hela cells were exposed to CoCl2 and treated with Erastin. Cell viability was detected by MTT assay, and concentrations of iron ion, MDA and GSH were determined using corresponding kits. Expressions of KDM4A, HIF1α, TfR1, DMT1, and H3k9me3 were detected by RT-qPCR, Western blot, and ChIP assay. The correlation of KDM4A and HIF1α was analyzed on Oncomine, UALCAN, and Starbase. CC cells were co-transfected with shKDM4A or/and pcDNA3.1-HIF1α. Iron uptake and release were assessed using the isotopic tracer method. The binding relationship between HIF1α and HRE sequence was verified by dual-luciferase assay. Results Cell viability and GSH were decreased while iron concentration, MDA, KDM4A, and HIF1α levels were increased in hypoxia conditions. The 2-h hypoxia induced ferroptosis resistance. KDM4A and HIF1α were highly-expressed in CC tissues and positively correlated with each other. KDM4A knockdown attenuated cell resistance to Erastin, increased H3K9me3 level in the HIF1α promoter region, and downregulated HIF1α transcription and translation. H3K9me3 level was increased in the HIF1α promoter after hypoxia. HIF1α overexpression abrogated the function of KDM4A knockdown on ferroptosis in hypoxia conditions. Iron uptake/release and TfR1/DMT1 levels were increased after hypoxia. Hypoxia activated HRE sequence in TfR1 and DMT1 promoters. Conclusion Hypoxia upregulated KDM4A, enhanced HIF1α transcription, and activated HRE sequence in TfR1 and DMT1 promoters via H3K9me3, thus inducing ferroptosis resistance in CC cells.
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3,3′-Diindolylmethane induces ferroptosis by BAP1–IP3R axis in BGC-823 gastric cancer cells. Anticancer Drugs 2022; 33:362-370. [DOI: 10.1097/cad.0000000000001270] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Luan Z, Morimoto Y, Fushimi A, Yamashita N, Suo W, Bhattacharya A, Hagiwara M, Jin C, Kufe D. MUC1-C dictates neuroendocrine lineage specification in pancreatic ductal adenocarcinomas. Carcinogenesis 2022; 43:67-76. [PMID: 34657147 PMCID: PMC8832436 DOI: 10.1093/carcin/bgab097] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/22/2021] [Accepted: 10/15/2021] [Indexed: 01/16/2023] Open
Abstract
Pancreatic ductal adenocarcinomas (PDAC) and poorly differentiated pancreatic neuroendocrine (NE) carcinomas are KRAS mutant malignancies with a potential common cell of origin. PDAC ductal, but not NE, lineage traits have been associated with cell-intrinsic activation of interferon (IFN) pathways. The present studies demonstrate that the MUC1 C-terminal subunit (MUC1-C), which evolved to protect mammalian epithelia from loss of homeostasis, is aberrantly overexpressed in KRAS mutant PDAC tumors and cell lines. We show that MUC1-C is necessary for activation of the type I and II IFN pathways and for expression of the Yamanaka OCT4, SOX2, KLF4 and MYC (OSKM) pluripotency factors. Our results demonstrate that MUC1-C integrates IFN signaling and pluripotency with NE dedifferentiation by forming a complex with MYC and driving the (i) achaete-scute homolog 1 and BRN2/POU3F2 neural, and (ii) NOTCH1/2 stemness transcription factors. Of translational relevance, targeting MUC1-C genetically and pharmacologically in PDAC cells (i) suppresses OSKM, NE dedifferentiation and NOTCH1/2, and (ii) inhibits self-renewal capacity and tumorigenicity. In PDAC tumors, we show that MUC1 significantly associates with activation of IFN signaling, MYC and NOTCH, and that upregulation of the MUC1-C → MYC pathway confers a poor prognosis. These findings indicate that MUC1-C dictates PDAC NE lineage specification and is a potential target for the treatment of recalcitrant pancreatic carcinomas with NE dedifferentiation.
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Affiliation(s)
- Zhou Luan
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | | | - Atsushi Fushimi
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan
| | - Nami Yamashita
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Wenhao Suo
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Pathology, The First Affiliated Hospital, Xiamen University, Xiamen, Fujian, China
| | | | - Masayuki Hagiwara
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Urology, Keio University Medical School, Tokyo, Japan
| | - Caining Jin
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Donald Kufe
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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Zhou X, Suo F, Haslinger K, Quax WJ. Artemisinin-Type Drugs in Tumor Cell Death: Mechanisms, Combination Treatment with Biologics and Nanoparticle Delivery. Pharmaceutics 2022; 14:395. [PMID: 35214127 PMCID: PMC8875250 DOI: 10.3390/pharmaceutics14020395] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/04/2022] [Accepted: 02/07/2022] [Indexed: 02/04/2023] Open
Abstract
Artemisinin, the most famous anti-malaria drug initially extracted from Artemisia annua L., also exhibits anti-tumor properties in vivo and in vitro. To improve its solubility and bioavailability, multiple derivatives have been synthesized. However, to reveal the anti-tumor mechanism and improve the efficacy of these artemisinin-type drugs, studies have been conducted in recent years. In this review, we first provide an overview of the effect of artemisinin-type drugs on the regulated cell death pathways, which may uncover novel therapeutic approaches. Then, to overcome the shortcomings of artemisinin-type drugs, we summarize the recent advances in two different therapeutic approaches, namely the combination therapy with biologics influencing regulated cell death, and the use of nanocarriers as drug delivery systems. For the former approach, we discuss the superiority of combination treatments compared to monotherapy in tumor cells based on their effects on regulated cell death. For the latter approach, we give a systematic overview of nanocarrier design principles used to deliver artemisinin-type drugs, including inorganic-based nanoparticles, liposomes, micelles, polymer-based nanoparticles, carbon-based nanoparticles, nanostructured lipid carriers and niosomes. Both approaches have yielded promising findings in vitro and in vivo, providing a strong scientific basis for further study and upcoming clinical trials.
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Affiliation(s)
| | | | - Kristina Haslinger
- Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands; (X.Z.); (F.S.)
| | - Wim J. Quax
- Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands; (X.Z.); (F.S.)
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31
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Metabolic regulation of ferroptosis in the tumor microenvironment. J Biol Chem 2022; 298:101617. [PMID: 35065965 PMCID: PMC8892088 DOI: 10.1016/j.jbc.2022.101617] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 01/09/2022] [Accepted: 01/10/2022] [Indexed: 12/15/2022] Open
Abstract
Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death triggered by impaired redox and antioxidant machinery and propagated by the accumulation of toxic lipid peroxides. A compendium of experimental studies suggest that ferroptosis is tumor-suppressive. Sensitivity or resistance to ferroptosis can be regulated by cell-autonomous and non-cell-autonomous metabolic mechanisms. This includes a role for ferroptosis that extends beyond the tumor cells themselves, mediated by components of the tumor microenvironment, including T cells and other immune cells. Herein, we review the intrinsic and extrinsic factors that promote the sensitivity of cancer cells to ferroptosis and conclude by describing approaches to harness the full utility of ferroptotic agents as therapeutic options for cancer therapy.
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32
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Ge C, Zhang S, Mu H, Zheng S, Tan Z, Huang X, Xu C, Zou J, Zhu Y, Feng D, Aa J. Emerging Mechanisms and Disease Implications of Ferroptosis: Potential Applications of Natural Products. Front Cell Dev Biol 2022; 9:774957. [PMID: 35118067 PMCID: PMC8804219 DOI: 10.3389/fcell.2021.774957] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 12/09/2021] [Indexed: 01/09/2023] Open
Abstract
Ferroptosis, a newly discovered form of regulatory cell death (RCD), has been demonstrated to be distinct from other types of RCD, such as apoptosis, necroptosis, and autophagy. Ferroptosis is characterized by iron-dependent lipid peroxidation and oxidative perturbation, and is inhibited by iron chelators and lipophilic antioxidants. This process is regulated by specific pathways and is implicated in diverse biological contexts, mainly including iron homeostasis, lipid metabolism, and glutathione metabolism. A large body of evidence suggests that ferroptosis is interrelated with various physiological and pathological processes, including tumor progression (neuro)degenerative diseases, and hepatic and renal failure. There is an urgent need for the discovery of novel effective ferroptosis-modulating compounds, even though some experimental reagents and approved clinical drugs have been well documented to have anti- or pro-ferroptotic properties. This review outlines recent advances in molecular mechanisms of the ferroptotic death process and discusses its multiple roles in diverse pathophysiological contexts. Furthermore, we summarize chemical compounds and natural products, that act as inducers or inhibitors of ferroptosis in the prevention and treatment of various diseases. Herein, it is particularly highlighted that natural products show promising prospects in ferroptosis-associated (adjuvant) therapy with unique advantages of having multiple components, multiple biotargets and slight side effects.
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Affiliation(s)
- Chun Ge
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Sujie Zhang
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Huiwen Mu
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shaojun Zheng
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Zhaoyi Tan
- Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Xintong Huang
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chen Xu
- Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Jianjun Zou
- Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Clinical Pharmacology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yubing Zhu
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- *Correspondence: Yubing Zhu, ; Dong Feng, ; Jiye Aa,
| | - Dong Feng
- Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
- Nanjing Southern Pharmaceutical Technology Co., Ltd., Nanjing, China
- *Correspondence: Yubing Zhu, ; Dong Feng, ; Jiye Aa,
| | - Jiye Aa
- Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
- *Correspondence: Yubing Zhu, ; Dong Feng, ; Jiye Aa,
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Yang F, Sun SY, Wang S, Guo JT, Liu X, Ge N, Wang GX. Molecular regulatory mechanism of ferroptosis and its role in gastrointestinal oncology: Progress and updates. World J Gastrointest Oncol 2022; 14:1-18. [PMID: 35116100 PMCID: PMC8790407 DOI: 10.4251/wjgo.v14.i1.1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/04/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) tumors, including liver, pancreatic, gastric, and colorectal cancers, have a high incidence rate and low survival rate due to the lack of effective therapeutic methods and frequent relapses. Surgery and postoperative chemoradiotherapy have largely reduced the fatality rates for most GI tumors, but these therapeutic approaches result in poor prognoses due to severe adverse reactions and the development of drug resistance. Recent studies have shown that ferroptosis plays an important role in the onset and progression of GI tumors. Ferroptosis is a new non-apoptotic form of cell death, which is iron-dependent, non-apoptotic cell death characterized by the accumulation of lipid reactive oxygen species (ROS). The activation of ferroptosis can lead to tumor cell death. Thus, regulating ferroptosis in tumor cells may become a new therapeutic approach for tumors, making it become a research hotspot. Current studies suggest that ferroptosis is mainly triggered by the accumulation of lipid ROS. Furthermore, several studies have indicated that ferroptosis may be a new approach for the treatment of GI tumors. Here, we review current research progress on the mechanism of ferroptosis, current inducers and inhibitors of ferroptosis, and the role of ferroptosis in GI tumors to propose new methods for the treatment of such tumors.
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Affiliation(s)
- Fan Yang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Si-Yu Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Sheng Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Jin-Tao Guo
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Xiang Liu
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Nan Ge
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Guo-Xin Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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Wang Q, Tang Y, Pan Z, Yuan Y, Zou Y, Zhang H, Guo X, Guo W, Huang X, Wu Z, Li C, Xu Q, Song J, Deng C. RNA-seq-based transcriptome analysis of the anti-inflammatory effect of artesunate in the early treatment of the mouse cerebral malaria model. Mol Omics 2022; 18:716-730. [DOI: 10.1039/d1mo00491c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The present study provides new insights into the molecular mechanisms by which artesunate improves prognosis in cerebral malaria, in particular inhibition of host cytokine storm.
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Affiliation(s)
- Qi Wang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- Institute of Pulmonary Disease, Guangzhou Chest Hospital, Guangzhou, Guangdong, P. R. China
| | - Yexiao Tang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, P. R. China
| | - Ziyi Pan
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Yueming Yuan
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- Institute of Science and Technology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Yuanyuan Zou
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Hongying Zhang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- Institute of Science and Technology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Xueying Guo
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Wenfeng Guo
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Xinan Huang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Zhibin Wu
- Institute of Science and Technology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Changqing Li
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Qin Xu
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Jianping Song
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Changsheng Deng
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
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35
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Selvarajoo N, Stanslas J, Islam MK, Sagineedu SR, Lian HK, Lim JCW. Pharmacological Modulation of Apoptosis and Autophagy in Pancreatic Cancer Treatment. Mini Rev Med Chem 2022; 22:2581-2595. [PMID: 35331093 DOI: 10.2174/1389557522666220324123605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/02/2022] [Accepted: 01/21/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Pancreatic cancer is a fatal malignant neoplasm with infrequent signs and symptoms until a progressive stage. In 2020, GLOBOCAN reported that pancreatic cancer accounts for 4.7% of all cancer deaths. Despite the availability of standard chemotherapy regimens for treatment, the survival benefits are not guaranteed because tumor cells become chemoresistant even due to the development of chemoresistance in tumor cells even with a short treatment course, where apoptosis and autophagy play critical roles. OBJECTIVE This review compiled essential information on the regulatory mechanisms and roles of apoptosis and autophagy in pancreatic cancer, as well as drug-like molecules that target different pathways in pancreatic cancer eradication, with an aim to provide ideas to the scientific communities in discovering novel and specific drugs to treat pancreatic cancer, specifically PDAC. METHOD Electronic databases that were searched for research articles for this review were Scopus, Science Direct, PubMed, Springer Link, and Google Scholar. The published studies were identified and retrieved using selected keywords. DISCUSSION/CONCLUSION Many small-molecule anticancer agents have been developed to regulate autophagy and apoptosis associated with pancreatic cancer treatment, where most of them target apoptosis directly through EGFR/Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. The cancer drugs that regulate autophagy in treating cancer can be categorized into three groups: i) direct autophagy inducers (e.g., rapamycin), ii) indirect autophagy inducers (e.g., resveratrol), and iii) autophagy inhibitors. Resveratrol persuades both apoptosis and autophagy with a cytoprotective effect, while autophagy inhibitors (e.g., 3-methyladenine, chloroquine) can turn off the protective autophagic effect for therapeutic benefits. Several studies showed that autophagy inhibition resulted in a synergistic effect with chemotherapy (e.g., a combination of metformin with gemcitabine/ 5FU). Such drugs possess a unique clinical value in treating pancreatic cancer as well as other autophagy-dependent carcinomas.
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Affiliation(s)
- Nityaa Selvarajoo
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Johnson Stanslas
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Mohammad Kaisarul Islam
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Sreenivasa Rao Sagineedu
- Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 57000 Kuala Lumpur, Malaysia
| | - Ho Kok Lian
- Department of Pathology, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Jonathan Chee Woei Lim
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
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Farmanpour-Kalalagh K, Beyraghdar Kashkooli A, Babaei A, Rezaei A, van der Krol AR. Artemisinins in Combating Viral Infections Like SARS-CoV-2, Inflammation and Cancers and Options to Meet Increased Global Demand. FRONTIERS IN PLANT SCIENCE 2022; 13:780257. [PMID: 35197994 PMCID: PMC8859114 DOI: 10.3389/fpls.2022.780257] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 01/03/2022] [Indexed: 05/05/2023]
Abstract
Artemisinin is a natural bioactive sesquiterpene lactone containing an unusual endoperoxide 1, 2, 4-trioxane ring. It is derived from the herbal medicinal plant Artemisia annua and is best known for its use in treatment of malaria. However, recent studies also indicate the potential for artemisinin and related compounds, commonly referred to as artemisinins, in combating viral infections, inflammation and certain cancers. Moreover, the different potential modes of action of artemisinins make these compounds also potentially relevant to the challenges the world faces in the COVID-19 pandemic. Initial studies indicate positive effects of artemisinin or Artemisia spp. extracts to combat SARS-CoV-2 infection or COVID-19 related symptoms and WHO-supervised clinical studies on the potential of artemisinins to combat COVID-19 are now in progress. However, implementing multiple potential new uses of artemisinins will require effective solutions to boost production, either by enhancing synthesis in A. annua itself or through biotechnological engineering in alternative biosynthesis platforms. Because of this renewed interest in artemisinin and its derivatives, here we review its modes of action, its potential application in different diseases including COVID-19, its biosynthesis and future options to boost production.
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Affiliation(s)
- Karim Farmanpour-Kalalagh
- Department of Horticultural Science, Faculty of Agriculture, Tarbiat Modares University, Tehran, Iran
| | - Arman Beyraghdar Kashkooli
- Department of Horticultural Science, Faculty of Agriculture, Tarbiat Modares University, Tehran, Iran
- *Correspondence: Arman Beyraghdar Kashkooli,
| | - Alireza Babaei
- Department of Horticultural Science, Faculty of Agriculture, Tarbiat Modares University, Tehran, Iran
| | - Ali Rezaei
- Department of Horticultural Science, Faculty of Agriculture, Tarbiat Modares University, Tehran, Iran
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Valashedi MR, Nikoo A, Najafi-Ghalehlou N, Tomita K, Kuwahara Y, Sato T, Roushandeh AM, Roudkenar MH. Pharmacological Targeting of Ferroptosis in Cancer Treatment. Curr Cancer Drug Targets 2021; 22:108-125. [PMID: 34856903 DOI: 10.2174/1568009621666211202091523] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/13/2021] [Accepted: 10/15/2021] [Indexed: 01/17/2023]
Abstract
Ferroptosis is a non-apoptotic mode of Regulated Cell Death (RCD) driven by excessive accumulation of toxic lipid peroxides and iron overload. Ferroptosis could be triggered by inhibiting the antioxidant defense system and accumulating iron-dependent Reactive Oxygen Species (ROS) that react with polyunsaturated fatty acids in abundance. Emerging evidence over the past few years has revealed that ferroptosis is of great potential in inhibiting growth and metastasis and overcoming tumor cell resistance. Thus, targeting this form of cell death could be perceived as a potentially burgeoning approach in cancer treatment. This review briefly presents the underlying mechanisms of ferroptosis and further aims to discuss various types of existing drugs and natural compounds that could be potentially repurposed for targeting ferroptosis in tumor cells. This, in turn, will provide critical perspectives on future studies concerning ferroptosis-based cancer therapy.
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Affiliation(s)
- Mehdi Rabiee Valashedi
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht. Iran
| | - Amirsadegh Nikoo
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht. Iran
| | - Nima Najafi-Ghalehlou
- Department of Medical Laboratory Sciences, Faculty of Paramedicine, Tabriz University of Medical Sciences, Tabriz. Iran
| | - Kazuo Tomita
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima. Japan
| | - Yoshikazu Kuwahara
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima. Iran
| | - Tomoaki Sato
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima. Iran
| | - Amaneh Mohammadi Roushandeh
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima. Iran
| | - Mehryar Habibi Roudkenar
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima. Iran
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38
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The Regulatory Effects and the Signaling Pathways of Natural Bioactive Compounds on Ferroptosis. Foods 2021; 10:foods10122952. [PMID: 34945503 PMCID: PMC8700948 DOI: 10.3390/foods10122952] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/19/2021] [Accepted: 11/22/2021] [Indexed: 12/15/2022] Open
Abstract
Natural bioactive compounds abundantly presented in foods and medicinal plants have recently received a remarkable attention because of their various biological activities and minimal toxicity. In recent years, many natural compounds appear to offer significant effects in the regulation of ferroptosis. Ferroptosis is the forefront of international scientific research which has been exponential growth since the term was coined. This type of regulated cell death is driven by iron-dependent phospholipid peroxidation. Recent studies have shown that numerous organ injuries and pathophysiological processes of many diseases are driven by ferroptosis, such as cancer, arteriosclerosis, neurodegenerative disease, diabetes, ischemia-reperfusion injury and acute renal failure. It is reported that the initiation and inhibition of ferroptosis plays a pivotal role in lipid peroxidation, organ damage, neurodegeneration and cancer growth and progression. Recently, many natural phytochemicals extracted from edible plants have been demonstrated to be novel ferroptosis regulators and have the potential to treat ferroptosis-related diseases. This review provides an updated overview on the role of natural bioactive compounds and the potential signaling pathways in the regulation of ferroptosis.
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Rishi G, Huang G, Subramaniam VN. Cancer: The role of iron and ferroptosis. Int J Biochem Cell Biol 2021; 141:106094. [PMID: 34628027 DOI: 10.1016/j.biocel.2021.106094] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 09/25/2021] [Accepted: 10/05/2021] [Indexed: 02/09/2023]
Abstract
Iron is an essential element for virtually all living things. Body iron levels are tightly controlled as both increased iron levels and iron deficiency are associated with many clinical conditions. Increased iron levels are associated with a worse prognosis in some cancers, so understanding the role of iron in cancer development has thus been an active area of research. Regulated forms of cell death are important in development and disease pathogenesis. In this Medicine in Focus review article, we discuss the role of iron in cancer, and ferroptosis, a new form of iron-regulated cell death triggered by increased iron and peroxidation of lipids. We also review the pathogenesis of cancer, potential therapeutics for targeting the increased requirement of iron, as well as how ferroptosis activation may have a role in treatment of cancers.
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Affiliation(s)
- Gautam Rishi
- Hepatogenomics Research Group, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Qld 4059, Australia
| | - Gary Huang
- Hepatogenomics Research Group, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Qld 4059, Australia
| | - V Nathan Subramaniam
- Hepatogenomics Research Group, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Qld 4059, Australia.
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40
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Yang Y, Zhang ZJ, Wen Y, Xiong L, Huang YP, Wang YX, Liu K. Novel perspective in pancreatic cancer therapy: Targeting ferroptosis pathway. World J Gastrointest Oncol 2021; 13:1668-1679. [PMID: 34853642 PMCID: PMC8603450 DOI: 10.4251/wjgo.v13.i11.1668] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/20/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a highly lethal malignancy with low resection and survival rates and is not sensitive to radiotherapy and chemotherapy. Ferroptosis is a novel form of nonapoptotic regulated cell death characterized by the accumulation of lipid peroxides and reactive oxygen species involved in iron metabolism. Ferroptosis has a significant role in the occurrence and development of various tumors. Previous studies have shown that regulating ferroptosis-induced cell death inhibited tumor growth in pancreatic cancer and was synergistic with other antitumor drugs to improve treatment sensitivity. Herein, we discuss the mechanism, inducers, and developments of ferroptosis in pancreatic cancer to provide new strategies for the treatment of the malignancy.
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Affiliation(s)
- Yang Yang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Zi-Jian Zhang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Yu Wen
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Li Xiong
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Yun-Peng Huang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Yong-Xiang Wang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Kai Liu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
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41
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Wei J, Zeng Y, Gao X, Liu T. A novel ferroptosis-related lncRNA signature for prognosis prediction in gastric cancer. BMC Cancer 2021; 21:1221. [PMID: 34774009 PMCID: PMC8590758 DOI: 10.1186/s12885-021-08975-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 11/05/2021] [Indexed: 01/21/2023] Open
Abstract
Background Gastric cancer (GC) is a common malignant cancer with a poor prognosis. Ferroptosis has been shown to play crucial roles in GC development. Long non-coding RNAs (lncRNAs) is also associated with tumor progression in GC. This study aimed to screen the prognostic ferroptosis-related lncRNAs and to construct a prognostic risk model for GC. Methods Ferroptosis-related lncRNAs from The Cancer Genome Atlas (TCGA) GC expression data was downloaded. First, single factor Cox proportional hazard regression analysis was used to select seven prognostic ferroptosis-related lncRNAs from TCGA database. And then, the selected lncRNAs were further included in the multivariate Cox proportional hazard regression analysis to establish the prognostic model. A nomogram was constructed to predict individual survival probability. Finally, we performed quantitative reverse transcription polymerase chain reaction (qRT-PCR) to verify the risk model. Results We constructed a prognostic ferroptosis-related lncRNA signature in this study. Kaplan-Meier curve analysis revealed a significantly better prognosis for the low-risk group than for the high-risk group (P = 2.036e-05). Multivariate Cox proportional risk regression analysis demonstrated that risk score was an independent prognostic factor [hazard ratio (HR) = 1.798, 95% confidence interval (CI) =1.410–2.291, P < 0.001]. A nomogram, receiver operating characteristic curve, and principal component analysis were used to predict individual prognosis. Finally, the expression levels of AP003392.1, AC245041.2, AP001271.1, and BOLA3-AS1 in GC cell lines and normal cell lines were tested by qRT-PCR. Conclusions This risk model was shown to be a novel method for predicting prognosis for GC patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08975-2.
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Affiliation(s)
- Jianming Wei
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Ye Zeng
- Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xibo Gao
- Department of Dermatology, Tianjin Children's Hospital, Tianjin, China
| | - Tong Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
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Li J, Chen X, Kang R, Zeh H, Klionsky DJ, Tang D. Regulation and function of autophagy in pancreatic cancer. Autophagy 2021; 17:3275-3296. [PMID: 33161807 PMCID: PMC8632104 DOI: 10.1080/15548627.2020.1847462] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/26/2020] [Accepted: 11/02/2020] [Indexed: 12/12/2022] Open
Abstract
Oncogenic KRAS mutation-driven pancreatic ductal adenocarcinoma is currently the fourth-leading cause of cancer-related deaths in the United States. Macroautophagy (hereafter "autophagy") is one of the lysosome-dependent degradation systems that can remove abnormal proteins, damaged organelles, or invading pathogens by activating dynamic membrane structures (e.g., phagophores, autophagosomes, and autolysosomes). Impaired autophagy (including excessive activation and defects) is a pathological feature of human diseases, including pancreatic cancer. However, dysfunctional autophagy has many types and plays a complex role in pancreatic tumor biology, depending on various factors, such as tumor stage, microenvironment, immunometabolic state, and death signals. As a modulator connecting various cellular events, pharmacological targeting of nonselective autophagy may lead to both good and bad therapeutic effects. In contrast, targeting selective autophagy could reduce potential side effects of the drugs used. In this review, we describe the advances and challenges of autophagy in the development and therapy of pancreatic cancer.Abbreviations: AMPK: AMP-activated protein kinase; CQ: chloroquine; csc: cancer stem cells; DAMP: danger/damage-associated molecular pattern; EMT: epithelial-mesenchymal transition; lncRNA: long noncoding RNA; MIR: microRNA; PanIN: pancreatic intraepithelial neoplasia; PDAC: pancreatic ductal adenocarcinoma; PtdIns3K: phosphatidylinositol 3-kinase; SNARE: soluble NSF attachment protein receptor; UPS: ubiquitin-proteasome system.
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Affiliation(s)
- Jingbo Li
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Xin Chen
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Herbert Zeh
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Daniel J. Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
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Effects of High-Flux Dialysis Combined with Hemoperfusion on Serum GRP78 and miR-495-3p in Renal Failure Patients. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9591177. [PMID: 34671680 PMCID: PMC8523225 DOI: 10.1155/2021/9591177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 11/18/2022]
Abstract
Objective This study was designed to probe into the changes and clinical significance of GRP78 and miR-495-3p in renal failure (RF) patients during high-flux dialysis (HFD) combined with hemoperfusion (HP). Methods Sixty-five RF patients and 74 health check-ups who were admitted in our hospital from March 2015 to February 2017 were prospectively selected, and the related characteristics were retrospectively collected for analysis. GRP78 and miR-495-3p were detected in RF patients at admission (before treatment), 12 weeks after treatment (during treatment), 24 weeks after treatment (after treatment), and the control group at admission, and the relationship between the two and the occurrence, efficacy, and recurrence of RF was analyzed. Results Before treatment, the GRP78 mRNA level in RF patients was higher than that in health check-ups, while the miR-495-3p level was lower (P < 0.05). GRP78 mRNA in RF patients was lower than that before treatment and was the lowest after treatment. On the contrary, miR-495-3p was higher than that before treatment and was the highest after treatment (P < 0.05). The two had a significant effect on predicting RF before treatment, efficacy of patients, and their recurrence after treatment (all P < 0.001). Conclusion GRP78 decreased during the treatment of high-flux hemodialysis (HF-HD) combined with systemic HP in RF patients, while miR-495-3p increased. Both of them have a good reference value for RF occurrence, treatment results, and recurrence.
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Zhao X, Chen F. Propofol induces the ferroptosis of colorectal cancer cells by downregulating STAT3 expression. Oncol Lett 2021; 22:767. [PMID: 34589146 PMCID: PMC8442167 DOI: 10.3892/ol.2021.13028] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 07/22/2021] [Indexed: 12/24/2022] Open
Abstract
Propofol is a commonly used intravenous anesthetic agent that can also suppress the proliferation of various human cancer types, including colorectal cancer (CRC). The present study aimed to investigate whether propofol could induce the ferroptosis of CRC cells by regulating signal transducer and activator of transcription 3 (STAT3). STAT3 expression in normal and CRC tissues was measured. Human normal colonic epithelial NCM460 cells and human CRC SW480 cells were exposed to different concentrations of propofol and then cell viability was detected. SW480 cells were transfected with a vector overexpressing STAT3 and treated with propofol, and the cell viability, colony formation, cell proliferation, iron level, ROS production and ferroptosis of these cells and control cells were evaluated. Overall, the results showed that STAT3 was highly expressed in CRC tissues. Propofol exerted no marked effect on NCM460 cell viability, but inhibited SW480 cell viability in a concentration-dependent manner. Meanwhile, STAT3 was downregulated by propofol in a concentration-dependent manner. Propofol also inhibited CRC cell proliferation and colony formation, and enhanced cellular iron and ROS levels. Additionally, the expression of proteins involved in ferroptosis was also altered by propofol, including the upregulation of CHAC1 and PTGS2 expression in CRC cells, and the inhibition of GPX4 expression. However, STAT3 overexpression blocked the effect of propofol on CRC cells. In conclusion, propofol may trigger the ferroptosis of CRC cells by downregulating STAT3 expression.
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Affiliation(s)
- Xining Zhao
- Department of Anesthesia, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Fei Chen
- Department of Anesthesiology, Mindong Hospital Affiliated to Fujian Medical University, Fu'an, Fujian 355000, P.R. China
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45
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Tang R, Wu Z, Rong Z, Xu J, Wang W, Zhang B, Yu X, Shi S. Ferroptosis-related lncRNA pairs to predict the clinical outcome and molecular characteristics of pancreatic ductal adenocarcinoma. Brief Bioinform 2021; 23:6374064. [PMID: 34553745 DOI: 10.1093/bib/bbab388] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/13/2021] [Accepted: 08/28/2021] [Indexed: 01/20/2023] Open
Abstract
Ferroptosis is a form of regulated cell death initiated by oxidative perturbations that can be blocked by iron chelators and lipophilic antioxidants, and ferroptosis may be the silver bullet treatment for multiple cancers, including immunotherapy- and chemotherapy-insensitive cancers such as pancreatic ductal adenocarcinoma (PDAC). Numerous studies have noted that long non-coding RNAs (lncRNAs) regulate the biological behaviour of cancer cells by binding to DNA, RNA and protein. However, few studies have reported the role of lncRNAs in ferroptosis processes and the function of ferroptosis-associated lncRNAs. The primary objective of the present study was to identify ferroptosis-related lncRNAs using bioinformatic approaches combined with experimental validation. The second objective was to construct a prognostic model to predict the overall survival of patients with PDAC. The present study identified ferroptosis-related lncRNAs using a bioinformatic approach and validated them in an independent pancreatic cancer cohort from Fudan University Shanghai Cancer Center. The lncRNA SLCO4A1-AS1 was identified as a novel molecule mediating ferroptosis resistance in vitro. A novel algorithm was used to construct a '0 or 1' matrix-based prognosis model, which showed promising diagnostic accuracy for potential clinical translation (area under the curve = 0.89 for the 2-year survival rate). Notably, molecular subtypes classified by the risk scores of the model did not belong to any previously reported subtypes of PDAC. The immune microenvironment, metabolic activities, mutation landscape and ferroptosis sensitivity were significantly distinct between patients with different risk scores. Sensitivity (IC50) to 30 common anticancer drugs was analysed between patients with different risks, and imatinib and axitinib were found to be potential drugs for the treatment of patients with lower risk scores. Overall, we developed an accurate prognostic model based on the expression patterns of ferroptosis lncRNAs, which may contribute greatly to the evaluation of patient prognosis, molecular characteristics and treatment modalities and could be further translated into clinical applications.
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Affiliation(s)
- Rong Tang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Zijian Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Zeyin Rong
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
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Bartolacci C, Andreani C, El-Gammal Y, Scaglioni PP. Lipid Metabolism Regulates Oxidative Stress and Ferroptosis in RAS-Driven Cancers: A Perspective on Cancer Progression and Therapy. Front Mol Biosci 2021; 8:706650. [PMID: 34485382 PMCID: PMC8415548 DOI: 10.3389/fmolb.2021.706650] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 08/02/2021] [Indexed: 01/17/2023] Open
Abstract
HRAS, NRAS and KRAS, collectively referred to as oncogenic RAS, are the most frequently mutated driver proto-oncogenes in cancer. Oncogenic RAS aberrantly rewires metabolic pathways promoting the generation of intracellular reactive oxygen species (ROS). In particular, lipids have gained increasing attention serving critical biological roles as building blocks for cellular membranes, moieties for post-translational protein modifications, signaling molecules and substrates for ß-oxidation. However, thus far, the understanding of lipid metabolism in cancer has been hampered by the lack of sensitive analytical platforms able to identify and quantify such complex molecules and to assess their metabolic flux in vitro and, even more so, in primary tumors. Similarly, the role of ROS in RAS-driven cancer cells has remained elusive. On the one hand, ROS are beneficial to the development and progression of precancerous lesions, by upregulating survival and growth factor signaling, on the other, they promote accumulation of oxidative by-products that decrease the threshold of cancer cells to undergo ferroptosis. Here, we overview the recent advances in the study of the relation between RAS and lipid metabolism, in the context of different cancer types. In particular, we will focus our attention on how lipids and oxidative stress can either promote or sensitize to ferroptosis RAS driven cancers. Finally, we will explore whether this fine balance could be modulated for therapeutic gain.
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Affiliation(s)
| | | | | | - Pier Paolo Scaglioni
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Scuto M, Trovato Salinaro A, Caligiuri I, Ontario ML, Greco V, Sciuto N, Crea R, Calabrese EJ, Rizzolio F, Canzonieri V, Calabrese V. Redox modulation of vitagenes via plant polyphenols and vitamin D: Novel insights for chemoprevention and therapeutic interventions based on organoid technology. Mech Ageing Dev 2021; 199:111551. [PMID: 34358533 DOI: 10.1016/j.mad.2021.111551] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/19/2021] [Accepted: 08/01/2021] [Indexed: 12/29/2022]
Abstract
Polyphenols are chemopreventive through the induction of nuclear factor erythroid 2 related factor 2 (Nrf2)-mediated proteins and anti-inflammatory pathways. These pathways, encoding cytoprotective vitagenes, include heat shock proteins, such as heat shock protein 70 (Hsp70) and heme oxygenase-1 (HO-1), as well as glutathione redox system to protect against cancer initiation and progression. Phytochemicals exhibit biphasic dose responses on cancer cells, activating at low dose, signaling pathways resulting in upregulation of vitagenes, as in the case of the Nrf2 pathway upregulated by hydroxytyrosol (HT) or curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Here, the importance of vitagenes in redox stress response and autophagy mechanisms, as well as the potential use of dietary antioxidants in the prevention and treatment of multiple types of cancer are discussed. We also discuss the possible relationship between SARS-CoV-2, inflammation and cancer, exploiting innovative therapeutic approaches with HT-rich aqueous olive pulp extract (Hidrox®), a natural polyphenolic formulation, as well as the rationale of Vitamin D supplementation. Finally, we describe innovative approaches with organoids technology to study human carcinogenesis in preclinical models from basic cancer research to clinical practice, suggesting patient-derived organoids as an innovative tool to test drug toxicity and drive personalized therapy.
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Affiliation(s)
- Maria Scuto
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy; Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy.
| | - Angela Trovato Salinaro
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy.
| | - Isabella Caligiuri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy.
| | - Maria Laura Ontario
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy.
| | - Valentina Greco
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy.
| | - Nello Sciuto
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy.
| | - Roberto Crea
- Oliphenol LLC., 26225 Eden Landing Road, Suite C, Hayward, CA 94545, USA.
| | - Edward J Calabrese
- Department of Environmental Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA, 01003, USA.
| | - Flavio Rizzolio
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; Department of Molecular Sciences and Nanosystems, Ca'Foscari University of Venice, 30123 Venezia, Italy.
| | - Vincenzo Canzonieri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy.
| | - Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy.
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Yang Y, Bai L, Liao W, Feng M, Zhang M, Wu Q, Zhou K, Wen F, Lei W, Zhang N, Huang J, Li Q. The role of non-apoptotic cell death in the treatment and drug-resistance of digestive tumors. Exp Cell Res 2021; 405:112678. [PMID: 34171351 DOI: 10.1016/j.yexcr.2021.112678] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 05/24/2021] [Accepted: 05/27/2021] [Indexed: 02/05/2023]
Abstract
Tumor cell apoptosis evasion is one of the main reasons for easy metastasis occurrence, chemotherapy resistance, and the low five-year survival rate of digestive system tumors. Current research has shown that non-apoptotic cell death plays an important role in tumors of the digestive system. Therefore, increasing the proportion of non-apoptotic tumor cells is one of the effective methods of improving therapeutic efficacies for digestive system tumors. Non-apoptotic cell death modes mainly include autophagic cell death, pyroptosis, ferroptosis, in addition to other cell death modes. This review covers a systematic review relating to the research progress made into autophagic cell death, pyroptosis, ferroptosis, and other cell death modes in the treatment of digestive system tumors. It also highlights how treatment is a reasonable prospect based on clinical experience and provides reliable guidance for the further development of digestive system tumor treatments.
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Affiliation(s)
- Yang Yang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - LiangLiang Bai
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Weiting Liao
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Mingyang Feng
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Mengxi Zhang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Qiuji Wu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Kexun Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Feng Wen
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Wanting Lei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Nan Zhang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Jiaxing Huang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China.
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Wang H, Lin D, Yu Q, Li Z, Lenahan C, Dong Y, Wei Q, Shao A. A Promising Future of Ferroptosis in Tumor Therapy. Front Cell Dev Biol 2021; 9:629150. [PMID: 34178977 PMCID: PMC8219969 DOI: 10.3389/fcell.2021.629150] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 04/26/2021] [Indexed: 12/24/2022] Open
Abstract
Currently, mechanisms and therapeutic approaches have been thoroughly studied in various prevalent malignant tumors, such as breast and lung cancer. However, there is inevitable tumor progression and drug resistance. Uncovering novel treatment strategies to inhibit tumor development is important. Ferroptosis, a form of cell death associated with iron and lipid peroxidation, has drawn extensive attention. In this paper, we reviewed the underlying mechanisms of ferroptosis (i.e., iron, glutathione, and lipid metabolism) and its role in various tumors (i.e., lung cancer, liver carcinoma, breast cancer, and pancreatic cancer). Moreover, we summarized ferroptosis-related anti-tumor drugs and emphasized the potential of combined treatment of anti-tumor drugs and radiotherapy in an effort to provide novel anti-tumor treatments.
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Affiliation(s)
- Hui Wang
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Danfeng Lin
- Department of Breast Surgery, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qianqian Yu
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhouqi Li
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Cameron Lenahan
- Burrell College of Osteopathic Medicine, Las Cruces, NM, United States
- Center for Neuroscience Research, Loma Linda University School of Medicine, Loma Linda, CA, United States
| | - Ying Dong
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qichun Wei
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Chen X, Kang R, Kroemer G, Tang D. Targeting ferroptosis in pancreatic cancer: a double-edged sword. Trends Cancer 2021; 7:891-901. [PMID: 34023326 DOI: 10.1016/j.trecan.2021.04.005] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/29/2021] [Accepted: 04/30/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains an aggressive malignancy with a 5-year survival rate below 10%. Its unique genetic makeup and tumor microenvironment produce a lack of response to current treatments, including chemotherapy, radiotherapy, and immunotherapy. Recent preclinical studies have revealed that ferroptosis, an iron-dependent form of nonapoptotic cell death driven by unrestricted lipid peroxidation, may be an attractive therapeutic goal in PDAC. Understanding the dual role of ferroptotic cell death in both promoting and suppressing tumor immunity, as well as its integrated regulatory mechanisms and signaling pathways, may lead to more effective treatment designs for clinical trials of PDAC and may minimize or delay the emergence of drug resistance or side effects.
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Affiliation(s)
- Xin Chen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, The Third Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China; Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Rui Kang
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe Labéllisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France; Suzhou Institute for Systems Biology, Chinese Academy of Sciences, Suzhou, China; Department of Women's and Children's Health, Karolinska University Hospital, 17176 Stockholm, Sweden.
| | - Daolin Tang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, The Third Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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